Major histocompatibility complex (MHC) encoded proteins and Killer cell immunoglobulin-like receptors (KIR) serve critical functions in innate immunity, adaptive immunity and reproduction. The combination of HLA class I and KIR genotype uniquely diversifies human immune systems and is strongly associated with infectious, allergic, autoimmune and inflammatory diseases as well as reproductive success. Because MHC and KIR genes evolve rapidly, Great Apes, the species most closely related to humans, are by far best model systems for immunogenetic and immunogenomic comparisons. But such studies have been limited to small numbers of captive animals that poorly represent the natural diversity and population structure. In a pioneering study of the Gombe population of wild chimpanzees, we uncovered deep evolutionary roots of a trans-species lineage of MHC-B alleles, that includes chimpanzee Patr-B*06 and human HLA-B*57 and protects against HIV/SIV disease progression. This demonstrates how studying wild ape populations reveals novel linkage and insight between structural variation and function. We propose to expand this analysis in two dimensions. First, we will deepen the analysis to encompass all MHC and KIR genes. Second, we will broaden the analysis to 43 populations that represent eight of the nine African Great Ape species and subspecies. Aim 1 will develop new methods for rapid acquisition of sequence data and its automated analysis. Aim 2 will produce a complete description of the African Great Ape KIR and MHC genes and their allelic diversity in natural populations. Analysis of these data will determine how the KIR receptors and their MHC class I ligands have co-evolved in African Great Apes and how this differs between species and subspecies. Aim 3 will connect immunogenetic diversity with functional outcomes associated with the variable occurrence of SIV in the African Great Ape populations. Longitudinal data from two well-studied chimpanzee populations will be used to identify factors associated with disease, survival and reproductive success. In sum, we propose a comprehensive analysis of the immunogenetics and immunogenomics of natural populations of the species most closely related to humans. The results will give new perspectives on the human immune system and greatly expand our knowledge of its strengths and weaknesses.